Roles of RNA m5C modification patterns in prognosis and tumor microenvironment infiltration of diffuse large B-cell lymphoma.

Genetic and epigenetic aberrations display an essential role in the initiation and progression of diffuse large B-cell lymphoma (DLBCL). 5-methylcytosine (m5C), a common RNA modification, regulates various cellular processes and contributes to tumorigenesis and cancer progression. However, m5C alterations in DLBCL remain unclear. Our research constructed an m5C prognostic model utilizing GEO data sets, which can efficiently predict the prognosis of patients with DLBCL, and verified the m5C prognostic model genes by immunohistochemistry analysis. This model was constructed using unsupervised consensus clustering analyses, Least Absolute Shrinkage and Selection Operator (LASSO), and multivariate Cox regression analyses. Based on the expression of m5C genes in the model, patients with DLBCL could be effectively divided into groups with significant survival time differences. The m5C risk-score signature demonstrated a highly significant independent prognostic value. Results from tumor microenvironment analyses revealed that m5C genes altered the infiltration of eosinophils, Tregs, and M2 macrophages. Additionally, they regulated T cell activation by modulating the expression of CTLA4, PDL1, B2M, CD8A, ICOS, and other relevant immune checkpoint expressions. In conclusion, our study presents a robust m5C prognostic model that effectively predicts prognosis in DLBCL. This model may offer a new approach for prognostic stratification and potential therapeutic interventions for patients with DLBCL.

DNA mismatch repair defect and intratumor heterogeneous deficiency differently impact immune responses in diffuse large B-cell lymphoma.

Deficient (d) DNA mismatch repair (MMR) is a biomarker predictive of better response to PD-1 blockade immunotherapy in solid tumors. dMMR can be caused by mutations in MMR genes or by protein inactivation, which can be detected by sequencing and immunohistochemistry, respectively. To investigate the role of dMMR in diffuse large B-cell lymphoma (DLBCL), MMR gene mutations and expression of MSH6, MSH2, MLH1, and PMS2 proteins were evaluated by targeted next-generation sequencing and immunohistochemistry in a large cohort of DLBCL patients treated with standard chemoimmunotherapy, and correlated with the tumor immune microenvironment characteristics quantified by fluorescent multiplex immunohistochemistry and gene-expression profiling. The results showed that genetic dMMR was infrequent in DLBCL and was significantly associated with increased cancer gene mutations and favorable immune microenvironment, but not prognostic impact. Phenotypic dMMR was also infrequent, and MMR proteins were commonly expressed in DLBCL. However, intratumor heterogeneity existed, and increased DLBCL cells with phenotypic dMMR correlated with significantly increased T cells and PD-1+ T cells, higher average nearest neighbor distance between T cells and PAX5+ cells, upregulated immune gene signatures, LE4 and LE7 ecotypes and their underlying Ecotyper-defined cell states, suggesting the possibility that increased T cells targeted only tumor cell subsets with dMMR. Only in patients with MYC¯ DLBCL, high MSH6/PMS2 expression showed significant adverse prognostic effects. This study shows the immunologic and prognostic effects of genetic/phenotypic dMMR in DLBCL, and raises a question on whether DLBCL-infiltrating PD-1+ T cells target only tumor subclones, relevant for the efficacy of PD-1 blockade immunotherapy in DLBCL.

Cord blood-derived CD19-specific chimeric antigen receptor T cells: an off-the-shelf promising therapeutic option for treatment of diffuse large B-cell lymphoma.

Purpose: Autologous chimeric antigen receptor (CAR) T cell therapy is one of the most significant breakthroughs in hematological malignancies. However, a three-week manufacturing cycle and ineffective T cell dysfunction in some patients hinder the widespread application of auto-CAR T cell therapy. Studies suggest that cord blood (CB), with its unique biological properties, could be an optimal source for CAR T cells, providing a product with 'off-the-shelf' availability. Therefore, exploring the potential of CB as an immunotherapeutic agent is essential for understanding and promoting the further use of CAR T cell therapy. Experimental design: We used CB to generate CB-derived CD19-targeting CAR T (CB CD19-CAR T) cells. We assessed the anti-tumor capacity of CB CD19-CAR T cells to kill diffuse large B cell lymphoma (DLBCL) in vitro and in vivo. Results: CB CD19-CAR T cells showed the target-specific killing of CD19+ T cell lymphoma cell line BV173 and CD19+ DLBCL cell line SUDHL-4, activated various effector functions, and inhibited tumor progression in a mouse (BALB/c nude) model. However, some exhaustion-associated genes were involved in off-tumor cytotoxicity towards activated lymphocytes. Gene expression profiles confirmed increased chemokines/chemokine receptors and exhaustion genes in CB CD19-CAR T cells upon tumor stimulation compared to CB T cells. They indicated inherent changes in the associated signaling pathways in the constructed CB CAR T cells and targeted tumor processes. Conclusion: CB CD19-CAR T cells represent a promising therapeutic strategy for treating DLBCL. The unique biological properties and high availability of CB CD19-CAR T cells make this approach feasible.

Prognostic and therapeutic value of serum lipids and a new IPI score system based on apolipoprotein A-I in diffuse large B-cell lymphoma.

Lipid metabolism is associated with lymphomagenesis and functions as a new therapeutic target in patients with lymphoma. Several serum lipids and lipoproteins have prognostic value in solid tumors; however, their value in diffuse large B-cell lymphoma (DLBCL) has been poorly described. We retrospectively analyzed and compared pre-treatment serum lipid and lipoprotein levels, including triacylglycerol (TG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), apolipoprotein A-I (ApoA-I), and apolipoprotein B (ApoB) between 105 DLBCL and 105 controls (no DLBCL). The prognostic significance of serum lipid and lipoprotein levels was determined using univariate and multivariate Cox proportional hazards models. The primary outcomes, overall survival (OS) and progression-free survival (PFS), were assessed by the Kaplan-Meier method. We combined the International Prognostic Index (IPI) with ApoA-I to build a nomogram model (IPI-A) to predict the OS and PFS of DLBCL. Serum TG, LDL-C, HDL-C, ApoA-I, and ApoB levels were significantly lower in the DLBCL patients than in controls and significantly increased after chemotherapy. Multivariate analyses showed that the ApoA-I level was an independent predictor of OS and PFS. In addition, our findings indicated that the prognostic index IPI-A significantly improves risk prediction over the traditional IPI score system. ApoA-I is an independent prognostic factor associated with poor OS and PFS in DLBCL patients. Our findings suggested that IPI-A is a prognostic index accurately used for risk assessment in patients with DLBCL.

Primary Diffuse Large B-Cell Lymphoma of the Penis: A Case and Literature Review.

Primary diffuse large B-cell lymphoma (DLBCL) of the penis is an exceptionally rare malignant disorder, and less than 20 cases have been previously reported. The diagnosis can be difficult, and the standard treatment has not been established yet. We reported an 86-year-old male patient with DLBCL of the penis with an annular penile ulcer, which was not sensitive to the classic R-C(H)OP regimen for three circles; then underwent surgical resection and achieved complete remission for 73 months until now. Including our patient, we collected the clinical characteristics of 20 patients with primary DLBCL of the penis. The median age was 69 years, and most patients manifested mass, diffuse swelling, non-healing ulcer in the penis, and difficulty with urination. Chemo-immunology and radiography were used as first-line therapy, and surgery still plays an essential role in refractory or recurrence. Due to its anatomical independence and physiological particularity, there is still no standard for diagnosing and treating primary DLBCL of the penis. Systemic chemotherapy and radiography were considered first-line therapy to induce remission and preserve the structure and function of the penile; however, surgery still plays a vital role in the refractory or recurrence of single extranodal lymphoma.

Identification of Aging-Related Genes Associated with Prognostic Value and Immune Microenvironment Characteristics in Diffuse Large B-Cell Lymphoma.

Diffuse large B-cell lymphoma (DLBCL) is a complex invasive tumour that occurs mainly among the elderly. Therefore, we analysed the relationship between ageing-related genes (AG) and DLBCL prognosis. Datasets related to DLBCL and human AGs were downloaded and screened from the Gene Expression Omnibus (GEO) database and HAGR website, respectively. LASSO and Cox regression were used to analyse AGs in the dataset and construct an AG predictive model related to DLBCL prognosis. Gene Ontology and the Kyoto Encyclopedia of Genes and Genomes enrichment were used to analyse the function of the AG predictive model. The immune microenvironment and immune cell infiltration in DLBCL and their relationship with the AG prediction model were also analysed. After the analysis, 118 AGs were identified as genes related to DLBCL prognosis. Using the LASSO and Cox regression analyses, 9 AGs (PLAU, IL7R, MYC, S100B, IGFBP3, NR3C1, PTK2, TBP, and CLOCK) were used to construct an AG prognostic model. In the training and verification sets, this model exhibited excellent predictive ability for the prognosis of patients with DLBCL who have different clinical characteristics. Further analysis revealed that the high- and low-risk groups of the AG prognostic model were significantly correlated with immune cell infiltration and tumour microenvironment in DLBCL. Functional enrichment analysis also showed that the genes in the AG model were associated with immune-related functions and pathways. In conclusion, we constructed an AG model with a strong predictive function in DLBCL, with the ability to predict the prognosis of patients with different clinical features. This model provides new ideas and potential therapeutic targets for the study of the pathogenesis of DLBCL.

HDAC inhibitor chidamide synergizes with venetoclax to inhibit the growth of diffuse large B-cell lymphoma via down-regulation of MYC, BCL2, and TP53 expression.

Diffuse large B-cell lymphoma (DLBCL) is an aggressive type of non-Hodgkin's lymphoma. A total of 10%‒15% of DLBCL cases are associated with myelocytomatosis viral oncogene homolog(MYC) and/or B-cell lymphoma-2 (BCL2) translocation or amplification. BCL2 inhibitors have potent anti-tumor effects in DLBCL; however, resistance can be acquired through up-regulation of alternative anti-apoptotic proteins. The histone deacetylase (HDAC) inhibitor chidamide can induce BIM expression, leading to apoptosis of lymphoma cells with good efficacy in refractory recurrent DLBCL. In this study, the synergistic mechanism of chidamide and venetoclax in DLBCL was determined through in vitro and in vivo models. We found that combination therapy significantly reduced the protein levels of MYC, TP53, and BCL2 in activated apoptotic-related pathways in DLBCL cells by increasing BIM levels and inducing cell apoptosis. Moreover, combination therapy regulated expression of multiple transcriptomes in DLBCL cells, involving apoptosis, cell cycle, phosphorylation, and other biological processes, and significantly inhibited tumor growth in DLBCL-bearing xenograft mice. Taken together, these findings verify the in vivo therapeutic potential of chidamide and venetoclax combination therapy in DLBCL, warranting pre-clinical trials for patients with DLBCL.

Seven Glycolysis-Related Genes Predict the Prognosis of Patients With Pancreatic Cancer.

Objectives: To identify the key glycolysis-related genes (GRGs) in the occurrence and development of pancreatic ductal carcinoma (PDAC), and to construct a glycolysis-related gene model for predicting the prognosis of PDAC patients. Methodology: Pancreatic ductal carcinoma (PDAC) data and that of normal individuals were downloaded from the TCGA database and Genotype-Tissue Expression database, respectively. GSEA analysis of glycolysis-related pathways was then performed on PDAC data to identify significantly enriched GRGs. The genes were combined with other patient's clinical information and used to construct a glycolysis-related gene model using cox regression analysis. The model was further evaluated using data from the validation group. Mutations in the model genes were subsequently identified using the cBioPortal. In the same line, the expression levels of glycolysis related model genes in PDAC were analyzed and verified using immunohistochemical images. Model prediction for PDAC patients with different clinical characteristics was then done and the relationship between gene expression level, clinical stage and prognosis further discussed. Finally, a nomogram map of the predictive model was constructed to evaluate the prognosis of patients with PDAC. Results: GSEA results of the training set revealed that genes in the training set were significantly related to glycolysis pathway and iconic glycolysis pathway. There were 108 differentially expressed GRGs. Among them, 29 GRGs were closely related to prognosis based on clinical survival time. Risk regression analysis further revealed that there were seven significantly expressed glycolysis related genes. The genes were subsequently used to construct a predictive model. The model had an AUC value of more than 0.85. It was also significantly correlated with survival time. Further expression analysis revealed that CDK1, DSC2, ERO1A, MET, PYGL, and SLC35A3 were highly expressed in PDAC and CHST12 was highly expressed in normal pancreatic tissues. These results were confirmed using immunohistochemistry images of normal and diseases cells. The model could effectively evaluate the prognosis of PDAC patients with different clinical characteristics. Conclusion: The constructed glycolysis-related gene model effectively predicts the occurrence and development of PDAC. As such, it can be used as a prognostic marker to diagnose patients with PDAC.

Corrigendum: Seven Glycolysis-Related Genes Predict the Prognosis of Patients With Pancreatic Cancer.

[This corrects the article DOI: 10.3389/fcell.2021.647106.].